The Center for Applied Genomics (CAG) at The Children's Hospital of Philadelphia (CHOP) has established a pediatric biorepository with over 60,000 children consented for access to electronic health records (EHRs) with regular updates, re-contact, and high-density genome-wide association (GWA) array data. For this project, we have proposed five specific aims reflecting the workgroup mechanism of the eMERGE consortium. These will build upon substantive Preliminary Data derived during eMERGE II, where a series of GWA, sequencing, pharmacogenomics (PGx), EHR integration, and return-of-results (RoR) projects helped establish a platform for translational and eMERGE III efforts. In the first of these aims, we propose to continue to expand the eMERGE phenotype library and we propose four lead phenotypes: obesity, epilepsy, intellectual disability, and autism, in which we have a strong record in discovery, integration, and translation. Under specific aim 2, we propose to leverage CAG's position as a world-leader in genomics research to characterize rare variants in 2,000 CAG patients, where we have already catalogued several hundred rare variants in the accompanying Appendix. Leveraging this resource and expertise at CAG and eMERGE, we propose to return actionable findings to a minimum of ~160 parents (Specific Aim 3). This effort will build upon our existing RoR platform established during eMERGE II that returned results to parents of 160 CHOP children with autism, and to several hundred individuals with PGx risk profiles. Our fourth aim is to evaluate the health impact, cost-effectiveness and ELSI implications of RoR, and we aim to longitudinally track all families to whom results are returned at four time-points, leveraging existing resources and surveys developed with pediatric eMERGE partners. Finally, we propose a massive expansion of our EHR integration, established under eMERGE II, which also provide and integrate education resources for patients and medical professionals across the eMERGE network. Ultimately, we anticipate that the immediate outcome of these efforts will be improved healthcare for patients at CHOP and expanding to the entire eMERGE network. Further, with our eMERGE partners, we aim to establish a blueprint for integrating genomics and EHR data on such a scale that it will have real potential to fundamentally change medical practice in the US.